A sustainable procedure toward alkyl arylacetates: palladium-catalysed direct carbonylation of benzyl alcohols in organic carbonates

A sustainable procedure toward alkyl arylacetates: palladium-catalysed direct carbonylation of benzyl alcohols in organic carbonates

Green Chem., 2018, Advance Article
DOI: 10.1039/C7GC03619A, Communication

Yahui Li, Zechao Wang, Xiao-Feng Wu
A sustainable procedure for the synthesis of various alkyl arylacetates from benzyl alcohols has been developed

 

A sustainable procedure toward alkyl arylacetates: palladium-catalysed direct carbonylation of benzyl alcohols in organic carbonates

 

Yahui Li,^a  Zechao Wang^a  and  Xiao-Feng Wu*^ab 

Author affiliations

* Corresponding authors

^a Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany

^b Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People's Republic of China
E-mail: Xiao-Feng.Wu@catalysis.de

Abstract

A sustainable procedure for the synthesis of various alkyl arylacetates from benzyl alcohols has been developed. With palladium as the catalyst and organic carbonates as the green solvent and in situ activator, benzyl alcohols were carbonylated in an efficient manner without any halogen additives.

Ethyl 2-phenylacetate
1H NMR (300 MHz, Chloroform-d) δ 7.32 – 7.08 (m, 5H), 4.08 (q, J = 7.1 Hz, 2H), 3.54 (s, 2H), 1.18 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 171.61, 134.17, 129.24, 128.54, 127.03, 60.85, 41.45, 14.18.

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Unconventional Method for the Synthesis of 3-Carboxyethyl-4-formyl(hydroxy)-5-arylpyrazoles

Unconventional Method for Synthesis of 3-Carboxyethyl-4-formyl(hydroxy)-5-aryl-N-arylpyrazoles

Michael J. V. da Silva^†, Julia Poletto^†, Andrey P. Jacomini^†, Karlos E. Pianoski^†, Davana S. Gonçalves^†, Gessica M. Ribeiro^†, Samara M. de S. Melo^†, Davi F. Back^‡, Sidnei Moura^§, and Fernanda A. Rosa^*† 

^† Departamento de Química, Universidade Estadual de Maringá (UEM), 87030-900 Maringá, PR, Brazil

^‡ Departamento de Química, Universidade Federal de Santa Maria (UFSM), 97110-970 Santa Maria, RS, Brazil

^§ Instituto de Biotecnologia, Universidade de Caxias do Sul (UCS), 295070-560 Caxias do Sul, RS, Brazil

J. Org. Chem., 2017, 82 (23), pp 12590–12602

DOI: 10.1021/acs.joc.7b02361

Publication Date (Web): November 2, 2017

 

*E-mail: farosa@uem.br

Cite this:J. Org. Chem. 82, 23, 12590-12602

Abstract

An alternative highly regioselective synthetic method for the preparation of 3,5-disubstituted 4-formyl-N-arylpyrazoles in a one-pot procedure is reported. The methodology developed was based on the regiochemical control of the cyclocondensation reaction of β-enamino diketones with arylhydrazines.

Structural modifications in the β-enamino diketone system allied to the Lewis acid carbonyl activator BF₃ were strategically employed for this control. Also a one-pot method for the preparation of 3,5-disubstituted 4-hydroxymethyl-N-arylpyrazole derivatives from the β-enamino diketone and arylhydrazine substrates is described.

J. Org. Chem. 2017, 82, 12590

 

4-Formyl-N-arylpyrazole substrates occupy a prominent position in the field of organic synthesis since they are key intermediates in obtaining a wide range of biologically active compounds. Because of the synthetic versatility of the 4-formyl-N-arylpyrazole skeleton, their synthesis has been extensively explored. In an extension of their previously published research,

 

Rosa and co-workers at Universidade Estadual de Maringá described a one-pot synthetic method that regioselectively produced 3,5-disubstituted-4-formyl-N-arylpyrazoles . The β-enamino diketone starting materials were readily synthesized via published procedures. High regioselectivity was secured via the use of BF₃·OEt₂ as the carbonyl activator and a bulky amine as the enamine component. Acetonitrile proved to be the most suitable solvent for the reaction.

 

After an aqueous workup, the desired pyrazoles were obtained in excellent yields. A variety of functional groups were tolerated on the two aryl substituents. This operationally simple procedure afforded the 4-formyl-N-arylpyrazoles in high yields, regioselectively. Furthermore, the formyl group could be reduced in situ with sodium borohydride to generate the corresponding 4-hydroxymethyl-N-arylpyrazoles.

 

 

3-(Ethoxycarbonyl)-4-formyl-5-(4-nitrophenyl)-1-phenyl-1H-pyrazole (3a)

Light yellow solid; yield: 0.150 g (82%); mp 147.0–149.2 °C;

 

¹H NMR (300.06 MHz, CDCl₃) δ (ppm) 1.47 (t, 3H, J = 7.1 Hz, O–CH₂–CH₃), 4.54 (q, 2H, J = 7.1 Hz, O–CH₂-CH₃), 7.19–7.25 (m, 2H, Ph), 7.32–7.43 (m, 3H, Ph), 7.48 (d, 2H, J = 8.9 Hz, 4-NO₂C₆H₄), 8.19 (d, 2H, J = 8.9 Hz, 4-NO₂C₆H₄), 10.57 (s, 1H, CHO);

 

¹³C NMR (75.46 MHz, CDCl₃) δ (ppm) 14.4 (O–CH₂–CH₃), 62.3 (O-CH₂–CH₃), 122.0 (C4), 123.5 (4-NO₂C₆H₄), 125.9 (Ph), 129.5 (Ph), 129.6 (Ph), 131.8 (4-NO₂C₆H₄), 134.1 (4-NO₂C₆H₄), 137.8 (Ph), 143.5 (C5), 145.0 (C3), 148.4 (4-NO₂C₆H₄), 161.5 (COOEt), 186.6 (CHO);

 

HRMS (ESI+): calcd for C₁₉H₁₆N₃O₅⁺, [M+H]⁺: 366.1084, found 366.1101.

 

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(Z and E)-4-(Methylamino)-3-(4-nitrobenzoyl)-2-oxobut-3-enoic Acid Ethyl Ester

  

(Z and E)-4-(Methylamino)-3-(4-nitrobenzoyl)-2-oxobut-3-enoic Acid Ethyl Ester (2a)

Light yellow solid; yield: 0.276 g (90%); Z/E ratio in CDCl₃: 80/20; mp 143.8–145.3 °C;

 

 ¹H NMR (300.06 MHz, CDCl₃) δ (ppm) (Z) 1.29 (t, 3H, J = 7.2 Hz, O–CH₂–CH₃), 3.24 (dd, 3H, J = 5.2, 0.7 Hz, NH-CH₃), 4.17 (q, 2H, J = 7.2 Hz, O–CH₂-CH₃), 7.64 (dd, 1H, J = 14.1, 0.7 Hz, H4), 7.75 (d, 2H, J = 8.8 Hz, 4-NO₂C₆H₄), 8.28 (d, 2H, J = 8.9 Hz, 4-NO₂C₆H₄), 10.67 (bs, 1H, NH); (E) 1.14 (t, 3H, J = 7.2 Hz, O–CH₂–CH₃), 3.34 (dd, 3H, J = 5.2, 0.8 Hz, NH-CH₃), 3.81 (q, 2H, J = 7.2 Hz, O–CH₂-CH₃), 7.62 (d, 2H, J = 8.8 Hz, 4-NO₂C₆H₄), 8.20 (dd, 1H, J = 14.3, 0.8 Hz, H4), 8.23 (d, 2H, J= 8.8 Hz, 4-NO₂C₆H₄), 10.79 (bs, 1H, NH);

 

 ¹³C NMR (75.46 MHz, CDCl₃) δ (ppm) (Z) 13.9 (O–CH₂–CH₃), 37.2 (NH-CH₃), 61.8 (O-CH₂–CH₃), 107.0 (C3), 123.7, 129.5, 144.5, 149.2 (4-NO₂C₆H₄), 163.1 (C4), 164.9 (COOEt), 186.9 (C2), 190.8 (C3′); (E) 13.7 (O–CH₂–CH₃), 37.1 (NH-CH₃), 62.0 (O-CH₂–CH₃), 106.7 (C3), 123.4, 128.6, 146.4, 148.8 (4-NO₂C₆H₄), 163.3 (C4), 164.4 (COOEt), 183.3 (C2), 193.7 (C3′);

 

HRMS (ESI+): calcd for C₁₄H₁₅N₂O₆⁺, [M+H]⁺: 307.0925, found 307.0938.

J. Org. Chem., 2017, 82 (23), pp 12590–12602

DOI: 10.1021/acs.joc.7b02361

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(2R,4R)-Methyl-2-tert-butyl-1,3-thiazolidine-3-formyl-4-carboxylate

(2R,4R)-Methyl-2-tert-butyl-1,3-thiazolidine-3-formyl-4-carboxylate (18)

the resulting crude was purified by flash chromatography on silica gel (eluted by 30–50% ethyl acetate in hexane). The collected fractions were evaporated and recrystallized from diethyl ether–hexanes (1:1, v/v) to afford N-formyl thazolidine 18 (300 g, 90% yield, 97% HPLC purity) as colorless crystals.

 

1H NMR (400 MHz, CDCl3, mixture of conformers (7:1), major): δ 8.35 (s, 1H), 4.89 (t, J = 8.0 Hz, 1H), 4.74 (s, 1H), 3.77 (s, 3H), 3.34–3.24 (m, 2H), 1.03 (s, 9H) ppm.

 

13C NMR (100 MHz, CDCl3, mixture of conformers (7:1), major): δ 170.1, 162.8, 75.3, 61.6, 52.8, 38.7, 33.0, 26.5 ppm. HRMS (ESI) m/z calcd for C10H17NO3S (M+H)+ 232.1002, found 232.1001.

 

Process Development and Scale-up Total Synthesis of Largazole, a Potent Class I Histone Deacetylase Inhibitor

Qi-Yin Chen†‡§, Pravin R. Chaturvedi§, and Hendrik Luesch*†‡§ 

†Department of Medicinal Chemistry and ‡Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, Florida 32610, United States

§ Oceanyx Pharmaceuticals, Inc., Sid Martin Biotechnology Incubator, 12085 Research Drive, Alachua, Florida 32615, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00352

 

*E-Mail: luesch@cop.ufl.edu; Tel.: +1-352-273-7738; Fax: +1-352-273-7741.

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00352

Abstract

Herein we describe the research and development of the process for the scale-up total synthesis of largazole, a potent class I selective histone deacetylase (HDAC) inhibitor, a potential anticancer agent and also useful for the treatment of other disorders where transcriptional reprogramming might be beneficial. The synthetic route and conditions for each fragment and final product were modified and optimized to make them suitable for larger-scale synthesis. With the process we developed, hundreds of grams of each fragment and decagrams of final product largazole were synthesized in good to excellent yields. The final target largazole was obtained in 21% overall yield over eight steps based on the longest sequence with over 95% HPLC purity.

 

 

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Methyl (S)-2-(benzylideneamino)propanoate

Alanine, N-(phenylmethylene)-, methyl ester; AC1LRVOF; D-Alanine, N-(phenylmethylene)-, methyl ester; Methyl benzylidenealaninate; SCHEMBL8125280; N-[(E)-Benzylidene]-Ala-OMe
Molecular Formula:	C11H13NO2
Molecular Weight:	191.23 g/mol

1. 112674-72-3
2. 53933-42-9

Methyl (S)-2-(benzylideneamino)propanoate (1g)
970 mg (6.95 mmol, 1.0 eq) L-Alanine methyl ester hydrochloride, 700 µL (6.88 mmol, 0.99 eq) benzaldehyde, 1.06 mL (7.65 mmol, 1.1 eq) triethylamine and 7 mL CHCl3. Yield: 1.289 g (6.74 mmol, 97%), yellow viscous oil.

1 H-NMR (300 MHz, CDCl3): δ = 8.31 (s, 1H), 7.81-7.74 (m, 2H), 7.48-7.38 (m, 3H), 4.16 (q, 3 JHH = 6.8 Hz, 1H), 3.75 (s, 3H), 1.53 (d, 3 JHH = 6.8 Hz, 3H).

13C NMR (75 MHz, CDCl3): δ = 173.1, 163.1, 135.8, 131.3, 128.7, 128.6, 68.2, 52.4, 19.6.


1H NMR PREDICT

13 C NMR PREDICT

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O=C(OC)[C@H](C)/N=C/c1ccccc1

Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids

 

Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of [small alpha]-difluoromethyl-amino acids

Green Chem., 2018, 20,108-112
DOI: 10.1039/C7GC02913F, Communication

 Open Access

  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Manuel Kockinger, Tanja Ciaglia, Michael Bersier, Paul Hanselmann, Bernhard Gutmann, C. Oliver Kappe
Difluoromethylated esters, malonates and amino acids (including the drug eflornithine) are obtained by a gas-liquid continuous flow protocol employing the abundant waste product fluoroform as an atom-efficient reagent.

Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids

 

Manuel Köckinger,^a  Tanja Ciaglia,^a  Michael Bersier,^b  Paul Hanselmann,^b  Bernhard Gutmann*^ac  and  C. Oliver Kappe*^ac 

Author affiliations

* Corresponding authors

^a Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
E-mail: bernhard.gutmann@uni-graz.at, oliver.kappe@uni-graz.at

^b Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland

^c Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria

Abstract

Fluoroform (CHF₃) can be considered as an ideal reagent for difluoromethylation reactions. However, due to the low reactivity of fluoroform, only very few applications have been reported so far. Herein we report a continuous flow difluoromethylation protocol on sp³ carbons employing fluoroform as a reagent. The protocol is applicable for the direct C^α-difluoromethylation of protected α-amino acids, and enables a highly atom efficient synthesis of the active pharmaceutical ingredient eflornithine.
Methyl 3,3-(difluoro)-2,2-diphenylpropanoate (2a) The product mixtures were collected and the solvent removed in vacuo. The products were isolated by thin layer chromatography (dichloromethane/hexane = 3/2 (v/v)). Yield: 173 mg (0.62 mmol, 62%); 93% by 19F NMR ;light yellow viscous liquid. 1 H NMR (300 MHz, D2O): δ = 7.45 – 7.19 (m, 10H), 6.90 (t, 2 JHF = 55.0 Hz, 1H), 3.79 (s, 3H). 13C NMR (75 MHz, D2O): δ = 171.1, 136.3, 129.8, 128.3, 128.2, 115.6 (t, 1 JCF = 246.2 Hz), 64.7, 53.1.19F NMR (282 MHz, D2O):δ = -123.0 (d, 2 JHF = 55.0 Hz).
  

Conclusions

A gas–liquid continuous flow difluoromethylation protocol employing fluoroform as a reagent was reported. Fluoroform, a by-product of Teflon manufacture with little current synthetic value, is the most attractive reagent for difluoromethylation reactions. The continuous flow process allows this reaction to be performed within reaction times of 20 min with 2 equiv. of base and 3 equiv. of fluoroform. Importantly, the protocol allows the direct C^α-difluoromethylation of protected α-amino acids. These compounds are highly selective and potent inhibitors of pyridoxal phosphate-dependent decarboxylases. The starting materials are conveniently derived from the commercially available α-amino acid methyl esters, and the final products are obtained in excellent purities and yields after simple hydrolysis and precipitation. The developed process appears to be especially appealing for industrial applications, where atom economy, sustainability, reagent cost and reagent availability are important factors.

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Bio-derived production of cinnamyl alcohol via a three step biocatalytic cascade and metabolic engineering

 

Bio-derived production of cinnamyl alcohol via a three step biocatalytic cascade and metabolic engineering

Green Chem., 2018, Advance Article
DOI: 10.1039/C7GC03325G, Paper

Evaldas Klumbys, Ziga Zebec, Nicholas J. Weise, Nicholas J. Turner, Nigel S. Scrutton
Cascade biocatalysis and metabolic engineering provide routes to cinnamyl alcohol.

Bio-derived production of cinnamyl alcohol via a three step biocatalytic cascade and metabolic engineering

 

Evaldas Klumbys,^a  Ziga Zebec,^a  Nicholas J. Weise,^a  Nicholas J. Turner^a  and  Nigel S. Scrutton*^a 

* Corresponding authors

^a Manchester Institute of Biotechnology (MIB), School of Chemistry, The University of Manchester, 131 Princess Street, Manchester, UK
E-mail:nigel.scrutton@manchester.ac.uk

Evaldas Klumbys

Prof Nigel ScruttonScD, FRSC, FRSB

Professor of Enzymology and Biophysical Chemistry

• Affiliations:
• Chemical Biology and Biological ChemistrySchool of Chemistry
• Manchester Institute of BiotechnologyFaculty of Science and Engineering

• Links:
• Manchester Centre for Biophysics and Catalysis
• Manchester Institute of Biotechnology
• Scrutton Laboratory website
• SYNBIOCHEM Synthetic Biology Research Centre

• Email:
• Nigel.Scrutton@manchester.ac.uk

Phone: +44 (0) 161 306 5152

Full contact details

ORCID: 0000-0002-4182-3500

Abstract

The construction of biocatalytic cascades for the production of chemical precursors is fast becoming one of the most efficient approaches to multi-step synthesis in modern chemistry. However, despite the use of low solvent systems and renewably resourced catalysts in reported examples, many cascades are still dependent on petrochemical starting materials, which as of yet cannot be accessed in a sustainable fashion. Herein, we report the production of the versatile chemical building block cinnamyl alcohol from the primary metabolite and the fermentation product L-phenylalanine. Through the combination of three biocatalyst classes (phenylalanine ammonia lyase, carboxylic acid reductase and alcohol dehydrogenase) the target compound could be obtained in high purity, demonstrable at the 100 mg scale and achieving 53% yield using ambient temperature and pressure in an aqueous solution. This system represents a synthetic strategy in which all components present at time zero are biogenic and thus minimises damage to the environment. Furthermore we extend this biocatalytic cascade by its inclusion in an L-phenylalanine overproducing strain of Escherichia coli. This metabolically engineered strain produces cinnamyl alcohol in mineral media using glycerol and glucose as the carbon sources. This study demonstrates the potential to establish green routes to the synthesis of cinnamyl alcohol from a waste stream such as glycerol derived, for example, from lipase treated biodiesel.
(R)-3-amino-3-(3-fluorophenyl)propanoic acid (1c) 1H NMR (CDCl3): δ 7.16-7.31 (m, 5H, ArH), 6.50-6.54 (d, 1H, J = 16 Hz, C=CH), 6.23-6.30 (dt, 1H, J = 16, 8 Hz, C=CHCH2 ), 4.21-4.23 (dd, 2H, J = 8, 4 Hz, C=CHCH2); 13C NMR (CDCl3): 136.70, 131.09, 128.60, 128.54, 127.69, 126.48, 63.65.
 

////////////cinnamyl alcohol,  biocatalytic, metabolic engineering